Certain 2-aminobenzothiazoles

ABSTRACT

ANILIDES OF THE GENERAL FORMULA   R1-X-(PHENYLENE)-N(-R2)-CO-R3 AND   1,2-(-X-C(-N(-R2)-CO-R3)=N-)BENZENE &lt;--&gt;   1,2-(-X-C(-N=C(-R3)-O-R2)=N-)BENZENE   AND ACID ADDITION SALTS THEREOF, IN WHICH X IS OXYGEN OR SULPHUR, R1 IS A METHYL RADICAL WITH THE PROVISO THAT, WHEN X IS A SULPHUR ATOM, R1 IS SELECTED FROM METHYL RADICALS AND RADICALS OF THE FORMULA   -S-(PHENYLENE)-N(-R2)-CO-R3   R2 IS A   -(CH2)N-N(-R4)-R5   RADICAL WHERE N IS A WHOLE NUMBER FROM 2 TO 3 AND R4 AND R5 EACH REPRESENT A HYDROGEN ATOM OR AN ALKYL RADICAL OR TOGETHER WITH THE NITROGEN ATOM TO WHICH THEY ARE ATTACHED COMPLETE A MORPHOLINE, PIPERIDINE, PYRROLIDINE OR PIPERAZING RING SYSTEM, AND R3 IS AN ALKYL, ARYL, ARALKYL OR ARALKENYL RADICAL, ARE EFFECTIVE AS ANTI-DEPRESSANT AGENTS.

United States Patent ()ihce Patented Mar. 30, 1971 U.S. Cl 260-305 4Claims ABSTRACT OF THE DISCLOSURE Anilides of the general formula andacid addition salts thereof, in which X is oxygen or sulphur, R is amethyl radical with the proviso that, when X is a sulphur atom, R isselected from methyl radicals and radicals of the formula XRI Thisinvention relates to novel compounds which are substituted anilides orsubstituted aminobenzoxazoles or substituted aminobenzothiazoles, to aprocess for the preparation thereof and to pharmaceutical compositionscontaining such compounds.

The present invention provides compounds of the general formula R or R-lTI-R ITPRZ \N 0012 and acid addition and quaternary ammonium saltsthereof, in which X is oxygen or sulphur; R is a hydrogen or halogenatom or a nitro, alkyl, alkoxy or haloalkyl radical; R is a methylradical or, when X is a sulphur atom, R may be a radical of the formula,R is a radical where n is a whole number from 1 to 4 and R and R eachrepresent a hydrogen atom or an alkyl radical or together with thenitrogen atom to which they are attached complate a heterocyclic ringwhich may contain a further hetero atom and which may be substituted;and R is a substituted or unsubstituted alkyl, aryl, aralkyl oraralkenyl radical.

The new ad novel compounds of the present invention possess valuablepharmacological activity. In particular, these compounds in standardpharmacological procedures demonstrated activity on the central nervoussystem and the cardiovascular system and are useful as antidepressants.

One series of compounds provided by the invention is the series ofcompounds of the general formula Ia in which R is a methyl radical,

radical and -COR is an acyl radical which may be an alkanoyl, aroyl,aralkanoyl or aralkenoyl radical and X, R, n, R and R have the meaningsdefined above. The radical XR preferably is in the ortho position to theradical NR R A second series of compounds provided by the invention isthe series of disulphides of the general formula:

radical, COR is an acyl radical and R, n, R and R have the meaningsdefined above. A third series of compounds provided by the invention isthe series of compounds of the general Formulas Ib and Ic, where Xpreferably is a sulphur atom. It is to be understood that this series ofcompounds either have the Formula lb or the conjugated Formula Ic,depending on which form is the more stable one for a given compound. Wehave found that when R is an alkyl radical in this series of compoundsthe products generally are of Formula Ib but when R is an aryl radicalthe products are generally of the Formula Ic.

The novel compounds provided by the invention generally may be preparedby reacting an amide of the general formula XR R or R IITCOR vr N H(IVa) (IVb) (where R, R X and R have the meanings defined above) with acompound of the general formula.

R R (V) where n, R and R have the meanings defined above and Z is ahalogen atom or an equivalent radical such as an alkyl or aryl sulphonylradical. The reaction preferably is carried out in solution in anorganic solvent (e.g. dimethyl formamide) by forming an alkali metalsalt (e.g. the sodium or potassium salt) of the amide of Formula IVa orb and then reacting this salt with the amino alkyl or aminalkynyl halideof Formula V It is also possible to introduce a R4 CH2-CECCH2N/ groupinto a compound of Formula IVa or b by carrying out a Mannich reactionon a compound of the general formula x11 X R or R I]ICOR3 \/IITCOR30113-05011 urn-050E N (VIe) (where R, R R and X have the meaningsdefined above) using formaldehyde or paraformaldehyde and the amine offormula The starting materials of general Formula IVa or IVb, whichcontain a secondary amido group NHCOR can be prepared by acylating thecorresponding compounds, which contain a primary amino group, with an Racylating agent for example with the acid chloride of formula R COCl.The remaining reactants used in the foregoing reactions either are knowncompounds, which are commercially available or can be prepared bymethods known in the art, or are derivatives thereof 'which can beprepared by Well-known chemical procedures from appropriate startingmaterials following the methods described in the art for the knowncompounds.

In the compounds of general Formula I, R preferably is a hydrogen atom(i.e. the ring is unsubstituted) or is a halogen atom (e.g. chlorine orbromine), an alkyl radical containing up to 4 carbon atoms (e.g.methyl), an alkoxy radical containing up to 4 carbon atoms (e.g.methoxy), or a haloalkyl radical (e.g. trifluoromethyl) R is a methylradical or, when X is sulphur, R can be a radical of Formula II. Xpreferably is sulphur, but may be oxygen, and the radical -XR incompounds of Formula Ia preferably is in the ortho position to theradical -NR R The value of n in the side chain of R preferably is or 3,and R and R which can be the same or different, each is hydrogen or analkyl radical containing 1 to 4 carbon atoms (e.g. methyl ethyl orn-propyl), or together form a ring (for example a morpholine,piperidine, pyrrolidine, piperazine, or an N-alkyl or N-aryl piperazinering, such as an N-methyl or N-phenyl piperazine ring). The radical CORis an acyl radical which may 'be an alkanoyl (e.g. acetyl or propionyl),aroyl (e.g. benzoyl or substituted benzoyl), aralkanoyl (e.g.phenethoyl) or aralkenoyl (e.g. cinnamoyl).

Acid addition and quaternary ammonium salts of the compounds of generalFormulas Ia and b can be prepared by treating the bases with an acid ora quaternising agent. Preferred acids are inorganic acids such ashydrochloric acid and sulphuric acid, and organic acids such as fumaricacid.

The invention also provides a pharmaceutical composition comprising acompound of general Formulas Ia, lb or Ic or a salt thereof and apharmaceutically acceptable carrier. Any solid, liquid or cream likecarrier known in the art can be used, and the carrier and amount ofactive material used will depend on the particular compound chosen, andstandard pharmaceutical practice. The composition may for example be inthe form of a table, capsule, cream or solution.

In the pharmacological evaluation of the properties of the compounds ofthis invention, the effects in vivo of the compounds are tested in thefollowing tests.

(a) A rat is anaesthetised and the blood pressure, heart rate andrespiration are recorded. Blood pressure responses to the injection ofepinephrine, actylcholine and histamine are determined before and afteradministration of each dose of one of the compounds. Nictitatingmembrane responses to electrical stimulation are also recorded beforeand after administration. The compounds are injected intravenously indoses of 0.22 and 20 mg./ kg. approximately 30 minutes apart. This testmeasures the hypotensive activity.

The response to the highest drugs are observed for a minimum of twohours.

(b) A compound is administered to three mice at each of the followingdoses: 400, 127, 40- and 12.7 mg./kg.

The animals are watched for a minimum of two hours during which timesigns of general stimulation (i.e. increased spontaneous motor activityhyperactivity on tactile stimulation, twitching), general depression(i.e. decreased spontaneous motor activity, decreased respiration) andautonomic activity (i.e miosis, mydriasis, diarrhea) are noted. Theanimals are tested for changes in reflexes (i.e. flexor, estensor) andare rated by use of a pole climb and inclined screen for the presence ofsedation-ataxia The Eddy Hot-Plate method (Nathan B. Eddy and DorothyLeimbach, J. Pharmacol. Exper. Therap. 107; 385 1953) is used to testfor analgesia. The experiment is terminated by subjecting each animal toa maximal electrostock to test for anti-convulsant activity.

Test (b) is for general central nervous system activity.

(0) The anti-depressant activity was measured on septal rats by themethod of Brady J. V. and Nauta W. J. H. described in J. Comp. Physiol.and Psychiol, vol. 48, p. 412 (1955).

The compounds of the invention were found to have the activities set outhereinbefore.

When the compounds of this invention are employed as anti-depressantagents they may be administered to warm-blooded animals, e.g., mice,rats, rabbits, dogs, cats, monkeys, etc., alone or in combination withpharmacologically acceptable carriers, the proportion of which isdetermined by solubility and chemical nature of the compounds chosenroute of administration and standard biological practice. For example,they may be administered orally in the form containing such excipientsas starch, milk, sugar, and so forth. They may also be administeredorally in the form of solutions or they may be injected parenterally.For parenteral administration they may be used in the form of a sterilesolution or suspension containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosage substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects.

The following non-limiting examples illustrate the invention:

EXAMPLE 1 o-Methylthio-N- ,B-dimethylaminoethyl) acetanilideo-Methylthioacetanilide (1.84 g.) was added to a suspension of sodiumhydride (0.48 g. of a 50% oil dispersion) in 60 ml. of dimethylformamide (D.M.F.). After stirring at 70 C. for one hour, a solution of,B-dimethylaminoethyl chloride (prepared by neutralising 2.88 g. of thehydrochloride, approx. 0.02 mole) in toluene (30 ml.) was added and themixture stirred at 50 C. for two hours then allowed to stand overnight.

The mixture was poured into water (200 ml.) and extracted with toluene.The combined toluene extracts were then extracted with dilute (2 N)hydrochloric acid and dried (MgSO The combined hydrochloric acidextracts were basified with 10 N sodium hydroxide and the resulting oilextracted with ether. The ethereal extracts were dried (MgSO and theether removed in vacuo on a rotary evaporator to giveo-methylthio-N-dimethylaminoethyl-acetanilide as an oil.

The free base was dissolved in the minimum amount of ethanol andethereal hydrogen chloride added. The mixture was allowed to standovernight in the refrigerator, to give the hydrochloride of the titlecompound. Yield (1.4 g., 73%) M.P. 212.5 to 2l3.5 C.

Analysis.-Found (percent): C, 54.2; H, 7.1; N, 9.7; S, 10.9; C1, 12.25.C H N OSHCl (percent) requires: C, 54.2; H, 7.0; N, 9.8; S, 11.2; C1.12.35.

EXAMPLE 2 o-Methylthio-N- B-dirnethylaminoethyl) propionanilide Theprocedure of Example 1 was followed, but usingo-methylthiopropionanilide (1.95 g.), sodium hydride (0.96 g. of a 50%oil dispersion) and ,H-dimethylaminoethyl chloride (prepared from 2.9 g.of the hydrochloride) in D.M.F. (60 ml.) to give the title compound asthe hydrochloride. Yield (0.8 g., 13.8%) M.P. 1578 C Analysis.-Found(percent): C, 55.5; H, 7.8; N. 9.1; S, 10.7; C1, 11.6. C H N OS.HC1(percent) requires: C, 55.6; H, 7.7; N, 9.3; S, 10.6; C1, 11.7.

EXAMPLE 3 o-Methylthio-N- B-dirnethylaminoethyl benzanilide Theprocedure of Example 1 was followed, but using o-methylthiobenzanilide(2.4 g.) sodium hydride (0.48 g. as a 50% oil dispersion) and,B-dimethylaminoethyl chloride (prepared from 2.9 g. of thehydrochloride) in D.M.F. (60 ml.) to give the title compound as thehydrochloride monohydrate. Yield (0.4 g.), M.P. 1656 C.

Analysis.-Found (percent) C, 58.7; H, 7.0; N, 7.6; S, 9.0; Cl, 9.5. C HN OSHCLH O (percent) requires: C, 58.65; H, 6.85; N, 7.6; S, 8.7; Cl,9.6.

EXAMPLE 4 o-Methylthio-N-(fl-dimethylaminoethyl)phenylacetanilide Theprocedure of Example 1 was followed, but usingo-methylthiophenylacetanilide (136 g.), sodium hydride (0.65 g. of a 50%oil suspension) and p-dimethylaminoethyl chloride (prepared from 2.9 g.of the hydrochloride. Yield (2.5 g., 49.5%) M.P. 178-180 C.

Analysis.Found (percent): C, 62.2; H, 6.9; N, 7.8; S, 8.6; CI, 9.8. C HN O|S.HCl (percent) requires: C, 62.5; H, 6.9; N, 7.7; S, 8.8; CI. 9.7.

, EXAMPLE 5 o-Methylthio-N- (y-dimethylaminopropyl) acetanilide Theprocedure of Example 1 was followed, but using o-methylthioacetanilide(2.7 g.) sodium hydride (10.07 g. as a 50% oil dispersion) and'y-dimethylaminopropyl chloride (approx. 0.03 mole) in D.M.F. (45 ml.)to obtain the title compound as the hydrochloride, M.P. 1646 C. (Yield1.0 g., 33.4%).

Analysis.Found (percent) C, 55.7; H, 7.75; N, 9.4; CI, 11.9; S, 10.5. CH N OISHCI (percent) requires: C, 55.7; H, 7.7; N, 9.3; Cl. 11.7; S,10.6.

EXAMPLE 6 o-Methylthio-N- ('y-dimethylaminopropyl) propionanilideEXAMPLE 7 N-(B-Dimethylaminoethyl) -o-propionanisidide The procedure ofExample 1 was followed, but using o-propionanisidide (18 g.), sodiumhydride (0.48 g. of a 50% oil dispersion) and fl-dimethylaminoethylchloride (from 2.9 g. of the hydrochloride) in D.M.F. (2.0 mls.) toobtain the title compound as the hydrochloride. Yield 2.44 g. (85%M.P.154-6 C.

Analysis.-Found (percent): C, 58.5; H, 8.3; N, 9.6;

c1, 12.5. c,.,H, N o .Hc1 (percent) required: 0, 53.7;

H, 8.1; N, 9.8; Cl, 12.4.

EXAMPLE 8 N- (B-dimethylaminoethyl -Nbenzoxyl-o-anisidide The procedureof Example 1 was followed, but using o-benzoylanisidide (4.5 g.) sodiumhydride (0.96 g. as a 50% oil dispersion) and 3-dimethylaminoethylchloride (approx. 0.02 mole) in D.M.F. to obtain the title compound asthe hydrochloride. Yield 3.78 g. (57% Analysis.Found (percent) C, 63.3;H, 6.9; N, 8.5; Cl, 11.2. C H N O HCl (percent) requires: C, 64.6; H,6.9; N, 8.4; CI, 10.6.

EXAMPLE 9 N-[ -dimethylaminopropyl) ]-N-benzoyl-o-anisidide Theprocedure of Example 1 was followed, but using o-benzoylanisidide (5.54g.), sodium hydride (0.96 as a 50% oil dispersion) and'y-dimethylaminopropyl chloride (a prox. 0.02 mole) in D.M.F. to obtainthe title compound as the hydrochloride. Yield 2.7 g. (39%).

Analysis.Found (percent): C, 65.2; H, 7.3; N, 7.9;' CI, 10.1. C H N OHCl (percent) requires: C, 65.4;

H, 7.2; N, 8.0; CI, 10.0.

EXAMPLE 1O 2- N- (,B-dimethylaminoethyl) acetamido] benzothiazole Theprocedure of Example 1 was followed, but using 2 acetamidobenzothiazole(1.92 g.), sodium hydride (0.48 g. as a 50% oil suspension) andB-dirnethylamino ethyl chloride (approx. 0.02 mole) in D.M. F. (20 mls.)to give the title compound as the hydrochloride. Yield 1.27 g. (83%).

7 Analysis.Fund (percent): C, 51.9; H, 6.15; N, 13.9; S, 10.5; C1, 12.0.C H N OS.HCl (percent) requires: C, 52.1; H, 6.1; N, 14.0; S, 10.7; C1,11.9.

EXAMPLE 1 l fi-Dimethylaminoethyl- (N-2'-benzothiazolyl benzimidate Theprocedure of Example 1 was followed, but using 2-benzamidobenzothiazole(2.54 g.), sodium hydride (0.48 g. as a 50% oil suspension), andfi-dimethylaminoethyl chloride (approx. 0.02 mole) in D.M.F. to give thetitle compound (owing to the conjugated form being more stable) as thehydrochloride monohydrate. Yield 2.99 g. (83%).

Analysis.-Found (percent): C, 56.9; H, 5.8; N, 11.3; Cl, 9.4; S, 8.3. CH N OS.HCl.I-I O (percent) requires: C, 56.95; H, 8.85; N, 11.05; Cl.9.35; S, 8.45.

EXAMPLE 12 'y-Dimethylaminopropyl- (N-2 -benzothiazolyl) benzimidate Theprocedure of Example 1 was followed, but using 2 benzamidobenzothiazole(2.54 g.) sodium hydride (0.48 g. as a 50% oil suspension), and'y-dimethylaminopropyl chloride (approx. 0.02 mole) in D.M.F. to givethe title compound (owing to the conjugated form being more stable) asthe hydrochloride monohydrate. Yield 2.96 g. (79% Analysis.Fou11d(percent): C, 57.8; H, 6.15; N, 10.6. C H N OS.HCLH O (percent)requires: C, 58.0; H, 6.15; N, 10.7.

EXAMPLE 13 p-Methylthio-N-( ,G-dimethylaminoethyl) acetanilidep-Methylthioaniline 13.9 g.), acetic anhydride (40 ml.) and hydridine (2ml.) were warmed on a steam bath for 45 minutes, poured into water (500ml.) and allowed to stand for one hour. The mixture was neutralised withsodium bicarbonate cautiously, extracted into methylene chloride (3 X100 ml.) and dried over MgSO The solvent was removed on a rotaryevaporator to leave crystals (12.2 g., 68%) of p-methylthioacetanilide,M.P. 127.8 C.

The procedure of Example 1 was then followed, but usingp-methylthioacetanilide (1.81 g.), sodium hydride (0.48 g. as a 50% oildispersion), fl-dimethylaminoethyl chloride (approx. 0.02 mole from 2.9g. of the hydro chloride) in toluene (20 mls.) to give the titlecompound as the hydrochloride. Yield 1.7 g. (78% Analysis.--Found(percent): C, 54.0; H, 7.5; N, 9.7; S, 11.3. C H N OSHCI (percent)requires: C, 54.1; H, 7.35; N, 9.7; S, 11.1.

EXAMPLE l4 2,2-di- [N- (fl-dimethylaminoethyl) acetamido] diphenyldisulphide (a) o-arninobenzenethiol (12.5 g., 0.1 mole) was suspended in0.880 ammonium hydroxide (75 ml.) and air bubbled through fortwenty-four hours. The mixture set solid. The yellow solid was filteredoff and crystallised from aqueous ethanol to give yellow plates of2,2'-diaminodiphenyldisulphide, 6.88 g. (55%). M.P. 94-95" C.

(b) 2,2'-diaminodiphenyldisulphide (6.88 g.) was dissolved in aceticanhydride (30 ml.) and pyridine (2 drops) and the mixture then warmed ona steam bath for twenty minutes and then poured into water (150 ml.).The white solid that separated was filtered off and dried.crystallisation from aqueous acetic acid gave white needles of2,2-di-acetaminodiphenyldisulphide, 8.47 g.

(92%), M.P. 160-161" C.

(0) Sodium hydride (1.52 g., 0.024 mole of a 50% oil dispersion) wassuspended in dimethylforamide (25 ml.) and treated with2,2-di-acetaminodiphenyldisulphide (3.32 g., 0.01 mole) dissolved indimethyl formamide (25 ml.). The mixture was warmed to C. and stirredfor two hours, cooled and a solution of fl-dimethylaminoethyl chloride(prepared from 3.32 g. (0.03 mole) of the hydrochloride) in toluene (30ml.) added. The mixture was stirred at room temperature for eighteenhours and then poured into water (300 ml.) extracted with toluene (3ml.) the toluene extracts combined and extracted with 2 N hydrochloricacid (3 60 ml.). The combined acidic extracts were basified with 10 Nsodium hydroxide to give a dark oil. This was extracted with ether (3 50ml.), the ether extracts dried (MgSO and the ether removed in vacuo togive 2,2'-di[N( 3-dimethylaminoethyl)-acetamido]diphenyldisulphide as anoil, 1.92 g. (41). The dihydrochloride was prepared in the normal mannerand had M.P. -157 C. after recrystallisation from isopropyl alcohol.

Analysis.Found (percent): C, 52.7; H, 6.8; N, 10.1; C1, 13.0;18, 11.6. CH N O S 2HCl (percent) requires: C, 52.7; H, 6.6; N, 10.2; CI. 13.0; S,11.8.

We claim:

1. A compound selected from the group consisting of compounds of thegeneral formula and the pharmaceutically acceptable acid addition saltsthereof, in which R is a di-(lower alky1)amino-lower alkyl radical and Ris selected from the group consisting of lower alkyl and phenylradicals.

2. A compound according to claim 1, which is 2-[N-(fl-dimethylaminoethyl) acetamidobenzothiazole.

3. A compound according to claim 1 which is fi-dimethylaminoethyl-(N-2-benzothiazolyl) benzimidate 4. A compound according to claim 1which is v-dimethylaminopropyl-(N-2-benzothiazolyl)benzimidate.

References Cited UNITED STATES PATENTS 2,851,391 9/1958 Gerjovich et a1260-305 ALEX MAZEL, Primary Examiner R. I. GALLAGHER, Assistant ExaminerU.S. Cl. X.R.

